Abstract 182: HOP Lys 23 Asn Mutation causes Human Cardiomyopathy
HOP (Homeodomain-Only Protein) is a transcriptional regulator that is expressed in cardiac tissue and inhibits Serum Response Factor-dependent transcription. HOP-knock out mice and HOP overexpressing mice were previously created to evaluate the biological role of HOP in cardiac morphogenesis. However, the contribution of HOP to cardiac disease is unknown. We hypothesized a HOP gene mutation might cause inherited cardiomyopathies. To address this issue, we sequenced the coding regions of HOP in 96 dilated cardiomyopathy (DCM) patients and 32 hypertrophic cardiomyopathy patients. A missense variation Lys 23 Asn (K23N) was identified in a young proband with familial DCM. This Lys23 residue is evolutionally highly conserved from zebrafish to human. Additionally, this K23N variation was not identified in 360 normal chromosomes. To examine the pathophysiological concequences of this K23N variation, we created transgenic mice that express wild-type HOP (Tg-HOPWT) and mutant HOP (Tg-HOPK23N) in the heart under control of the alpha-MHC promoter, and compared their phenotypes. By 8 weeks of age, the hearts of Tg-HOPK23N mice were enlarged and had impaired contraction compared to Tg-HOPWT hearts even though the two strains expressed similar amounts of HOP protein. Tg-HOPK23N hearts contained elevated levels of ANF, BNP, skeletal actin and CARP mRNAs and reduced levels of SERCA2 mRNA, consistent with the molecular changes associated with heart failure. By 24 weeks of age, many Tg-HOPK23N die of heart failure with dramatic cardiac dilation and fibrosis. We conclude that a missense mutation (K23N) in HOP causes dilated cardiomyopathy in mouse and man and that HOP can be a DCM disease gene.